Aetiology and pathogenesis of cystic ovarian follicles in

dairy cattle: a review

Tom Vanholder, Geert Opsomer, Aart De Kruif

To cite this version:

Tom Vanholder, Geert Opsomer, Aart De Kruif. Aetiology and pathogenesis of cystic ovarian
follicles in dairy cattle: a review. Reproduction Nutrition Development, EDP Sciences, 2006,
46 (2), pp.105-119. <10.1051/rnd:2006003>. <hal-00900607>

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Reprod. Nutr. Dev. 46 (2006) 105119

INRA, EDP Sciences, 2006
DOI: 10.1051/rnd:2006003

105

Review

Aetiology and pathogenesis of cystic ovarian follicles

in dairy cattle: a review
Tom VANHOLDER, Geert OPSOMER*, Aart DE KRUIF
Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine,
Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
(Received 23 August 2005; accepted 5 December 2005)

Abstract Cystic ovarian follicles (COF) are an important ovarian dysfunction and a major cause
of reproductive failure in dairy cattle. Due to the complexity of the disorder and the heterogeneity
of the clinical signs, a clear definition is lacking. A follicle becomes cystic when it fails to ovulate
and persists on the ovary. Despite an abundance of literature on the subject, the exact pathogenesis
of COF is unclear. It is generally accepted that disruption of the hypothalamo-pituitary-gonadal axis,
by endogenous and/or exogenous factors, causes cyst formation. Secretion of GnRH/LH from the
hypothalamus-pituitary is aberrant, which is attributed to insensitivity of the hypothalamus-pituitary
to the positive feedback effect of oestrogens. In addition, several factors can influence GnRH/LH
release at the hypothalamo-pituitary level. At the ovarian level, cellular and molecular changes in
the growing follicle may contribute to anovulation and cyst formation, but studying follicular changes
prior to cyst formation remains extremely difficult. Differences in receptor expression between COF
and dominant follicles may be an indication of the pathways involved in cyst formation. The
genotypic and phenotypic link of COF with milk yield may be attributed to negative energy balance
and the associated metabolic and hormonal adaptations. Altered metabolite and hormone
concentrations may influence follicle growth and cyst development, both at the level of the
hypothalamus-pituitary and the ovarian level.
cystic ovarian follicles / pathogenesis / hypothalamus-pituitary / ovary / negative energy
balance

1. INTRODUCTION
Cystic ovarian follicles (COF) are an
important cause of subfertility in dairy cattle, since they extend the calving interval
[13]. Prolongation of the calving interval
and treatment costs of COF result in economic loss for the dairy farmer. In most of
the literature, COF are referred to as Cystic
Ovarian Disease (COD). However, this terminology should be revised since the emphasis on cystic follicles has shifted over time.

In the 1940s, the presence of cystic follicles on the ovaries was mainly associated
with nymphomania and a bull-like appearance in cows [4, 5], which are clear clinical
signs of a state of disease. Over the past
decades, dairy herd management and economics have evolved to a situation in which
fertility in the postpartum period is utterly
important. During this period, cystic follicles are rather common, and generally occur
without obvious clinical signs. Normal
ovarian cyclicity is, however, delayed and

* Corresponding author: Geert.Opsomer@Ugent.be

Article published by EDP Sciences and available at http://www.edpsciences.org/rnd or http://dx.doi.org/10.1051/rnd:2006003

106

T. Vanholder et al.

these cysts should therefore be regarded as

COD, despite the absence of previously
classical signs of disease in the majority
of cases. In addition, after a variable period
of time, cysts can become non-steroidogenic and then they no longer interfere with
cyclicity [6, 7]. Consequently, at the time
the non-steroidogenic cyst is observed, no
other clinical abnormalities are present.
In present-day dairy herd health programmes, cysts are often diagnosed in the
absence of clear clinical signs. Therefore the
term Cystic Ovarian Disease no longer
seems appropriate and should be replaced
by the term Cystic Ovarian Follicle(s)
which does not necessarily implicate a state
of disease. In this review, we will therefore
use COF instead of COD. We prefer to use
COF instead of ovarian cysts, because the
former term indicates that it is the ovarian
follicle(s) and not any other ovarian tissue
that becomes cystic.
2. DEFINITION
Cystic ovarian follicles develop when one
or more follicles fail to ovulate and subsequently do not regress but maintain growth
and steroidogenesis. They are defined as
follicle-like structures, present on one or both
ovaries, with a diameter of at least 2.5 cm
for a minimum of ten days in the absence
of luteal tissue [811]. It has become clear
though that this definition needs to be
revised. First, the size limit is rather artificial since follicles might already become
cystic at a smaller size, and dominant follicles ovulate on average at a size of 1.6 to
1.9 cm in dairy cows [1214]. Moreover,
many researchers showed that COF are actually dynamic structures, which can regress
and be replaced by new cysts [1518]. The
factors that determine whether a cyst will
regress or not, remain unknown [19, 20],
although changes in mean LH concentration seem to be involved [16]. So the
required individual persistency of ten days
is questionable. In addition, in practice, veterinarians generally do not have the oppor-

tunity to perform a second examination of

an animal ten days after the initial diagnosis
of COF to fulfill all the terms of the definition. The absence of a corpus luteum is
another requirement, which is not always
fulfilled [21]. Non-steroidogenic cysts which
are hormonally inactive do not influence
the normal oestrous cycle, so they can occur
together with a corpus luteum. Therefore,
recent research articles define COF differently and perhaps more logically [16, 2224],
although a generally accepted definition is
still lacking, which can also be attributed to
the heterogeneity (type of cyst, time of occurrence, clinical signs) of the cysts.
Based on the current knowledge and
recent literature, COF may be defined as follicles with a diameter of at least 2 cm that are
present on one or both ovaries in the absence
of any active luteal tissue and that clearly
interfere with normal ovarian cyclicity.
Macroscopically, cysts can be subdivided
into follicular and luteal cysts, which are
considered to be different forms of the same
disorder [25]. Luteal cysts are believed to
be follicular cysts in later stages [26]. Determination of progesterone concentrations in
blood plasma, milk or milk fat can help to
make a distinction between the two types.
Follicular cysts secrete little or no progesterone while luteal cysts clearly do [26].
However, the threshold values used in the
literature differ a lot [2731], which makes
it difficult to set a concentration threshold.
In addition, the many intermediate forms
with limited or extensive luteinisation do
not allow for a clear identification of cyst
type. So classification is not easy and is subject to personal interpretation. Ultrasound
can be useful in supplying extra information.
Follicular cysts have a thin wall ( 3 mm)
and the follicular fluid is uniformly anechogenic, while luteal cysts have a thicker wall
(> 3 mm), which is visible as an echogenic
rim. Also, the latter often have echogenic
spots and web-like structures in the follicular fluid [32, 33]. Luteal cysts should not
be confused with hollow corpora lutea,
which are not pathological at all [26].

Cystic ovarian follicles in dairy cattle

Hollow corpora lutea are just young corpora lutea with an antrum [34]. Ultrasound
examination of the ovaries is useful in making a distinction between a luteal cyst and
a cystic corpus luteum [32, 35].
Follicular cysts initially continue to produce oestrogens in the absence of other follicles > 5 mm on ultrasound [36]. After a
variable period of time oestrogen production
may cease. The cyst becomes non-steroidogenic without luteinising, thereby allowing a
new follicular wave to emerge and follicles
to grow beyond 5 mm [6, 7].

3. INCIDENCE AND SIGNS

Cystic ovarian follicles can occur at different times throughout lactation. The incidence varies between 6 and 30% [9, 11, 37
43]. The diagnosis of COF is most often
made during the first 60 days post partum
[8, 9, 38, 44], mainly because of the close
monitoring of cow fertility during this
period. The majority of all cysts occur
throughout this stage [37, 40, 43]. The selfrecovery percentage of these early cysts is
6065% [8, 9, 38, 43]. Despite this high
self-recovery rate, the importance in dairy
cow fertility is considerable [45]. As
reported by Thatcher and Wilcox [46] and
more recently by Shrestha et al. [47], early
resumption of ovarian cyclicity is beneficial for fertility. By delaying/interfering
with ovarian cyclicity, COF increase the
time to first insemination and the interval
from parturition to conception. In addition,
COF decrease the pregnancy rate after first
insemination and increase the number of
services per conception [47, 48].
A genetic predisposition exists for COF
[49, 50], but the heritability is rather low,
being 0.07 to 0.12 [5153]. However, the
incidence in Dutch Holstein Friesian herds
is actually increasing [51]). Genetic selection to reduce the incidence of COF can be
successful, despite the low heritability [54].
The clinical signs that accompany ovarian cysts are variable. Anoestrus is most

107

common, especially during the postpartum

period [9]. Irregular oestrus intervals, nymphomania, relaxation of the broad pelvic
ligaments and development of masculine
physical traits are other signs which may be
present, especially later during lactation
[11, 55].

4. PATHOGENESIS OF OVARIAN
CYSTS
Ovarian dysfunctions like cysts occur most
often during the early postpartum period
when there is a transition from the noncyclic condition during pregnancy to the
establishment of regular cyclicity. It is generally accepted that cystic follicles develop
due to a dysfunction of the hypothalamicpituitary-ovarian axis. This dysfunction has
a multifactorial etiology, in which genetic,
phenotypic and environmental factors are
involved [9, 19, 26]. When discussing the
pathogenesis of COF, a distinction may be
made between a primary defect in the
hypothalamus-pituitary and a primary defect
at the level of the ovary in the follicle itself.
However, COF formation may result from
defects in both ovary/follicle and the hypothalamus/pituitary as well.
4.1. Hypothalamic-pituitary
dysfunction
The most widely accepted hypothesis
explaining the formation of a cyst is that LH
release from the hypothalamus-pituitary is
altered: the pre-ovulatory LH-surge is either
absent, insufficient in magnitude or occurs
at the wrong time during dominant follicle
maturation, which leads to cyst formation
[8, 16, 18, 41] (Fig. 1). This aberrant LH
release does not seem to be caused by a
lower GnRH content of the hypothalamus,
nor by reduced GnRH receptor numbers or
LH content in the pituitary [56, 57].
It is believed that an altered feedback
mechanism of oestrogens on the hypothalamus-pituitary can result in an aberrant

108

T. Vanholder et al.

Figure 1. Schematic representation of the pathogenesis of ovarian cysts and the possible pathways
involved. An FSH surge stimulates the emergence of a new follicular wave, from which a single
dominant follicle is selected at the time of deviation. Through a positive feedback loop oestradiol
stimulates GnRH and LH pulsatility, which in turn supports growth and development of the dominant
follicle. Upon reaching preovulatory size, follicular steroidogenic activity reaches a peak and produces a preovulatory oestradiol surge. This surge either fails to elicit a GnRH and subsequent LH
surge or the GnRH/LH surge is mistimed/delayed. The dominant follicle, therefore, does not ovulate
but, due to the ongoing LH pulsatility, continues to grow and becomes a cyst. The disruption of the
hypothalamic-pituitary-gonadal axis can be caused by factors affecting the oestradiol feedback
mechanism and GnRH/LH release at the hypothalamic-pituitary level (1) and/or by an aberrant follicle growth and development with alterations in receptor expression and steroidogenesis (2), leading
to an altered oestradiol surge and feedback (3). Hypothalamic-pituitary function and follicular
growth/development may be affected by NEB through metabolic/hormonal adaptations. In addition,
in the situation of NEB, the expression of genetic hereditary factor(s) associated with COF may be
promoted or the functional importance may increase, which in turn may affect follicle growth and
hypothalamic-pituitary function.

GnRH/LH release and cyst formation. A

GnRH/LH surge occurring prematurely
during follicle growth, i.e. when no follicle
capable of ovulation is present, can render
the hypothalamus unresponsive to the feedback effect of oestradiol which results in the

formation of ovarian cysts [22, 58]. To restore

the feedback mechanism, the hypothalamus
needs to be exposed to progesterone [59, 60].
Consequently, a similar state of hypothalamic refractoriness to oestrogens and subsequent cyst formation can be achieved if

Cystic ovarian follicles in dairy cattle

the progesterone rise after a spontaneous

ovulation is prevented [61]. This physical
state of hypothalamic unresponsiveness to
oestrogens seems to be present in the majority of cows with COF, as illustrated by the
failure of an exogenous oestradiol treatment to elicit a timely LH surge [6265].
However, the refractoriness of the hypothalamus-pituitary for oestradiol in cows with
COF may be a consequence rather than a
cause of the disease. Removal of the cystic
ovary by ovariectomy restores the feedback
mechanism and the capacity of oestradiol to
elicit an LH surge, although the underlying
mechanism is not known [66].
An altered feedback mechanism and
GnRH/LH release may be attributed to factors
interfering at the hypothalamic-pituitary level.
Progesterone at suprabasal concentrations
blocks the LH-surge, thereby inhibiting ovulation, but increases the LH pulse frequency
[67, 68]. This results in an anovulatory, persistent follicle with a larger diameter and a
longer lifespan than normal, and increased
peripheral oestradiol concentrations [68].
These follicular and hormonal changes are
very similar to observations made in cows
with COF [16]. Recently, Hatler et al. [23]
observed that at the time of diagnosis, most
cysts are accompanied by suprabasal progesterone concentrations, which play a role
in cyst turnover. These observations together
with the similarities between persistent
follicles, induced by suprabasal progesterone,
and naturally occurring cysts, suggest a role
for progesterone in the pathogenesis of COF.
However, suprabasal progesterone profiles
seem to play a limited role in primary COF
formation [69]. Factors indirectly reducing
GnRH/LH secretion like stress [6, 7072],
intrauterine infections [44, 73] and seasonality [74] are also considered to increase the
risk of cyst formation.
In cystic cows, the formation of new cysts
is accompanied by increased LH pulse frequencies and amplitudes [16, 57]. However
hypersecretion of LH does not seem to be
involved in cyst formation, but it may play
a role in cyst persistence [75]. Data obtained

109

in sheep also dismiss an increased LH secretion as a primary cause of COF [76].

In conclusion, an aberrant LH surge is
likely to be the trigger for the development
of COF. Abnormal LH release seems to be
caused by an altered feedback mechanism
of oestrogens on the hypothalamus-pituitary.
The malfunctioning of the feedback mechanism can be caused by factors directly interfering at the hypothalamic-pituitary level or
by an altered follicle growth and development disrupting the hypothalamic-pituitarygonadal axis, as discussed below.
4.2. Ovarian/follicular dysfunction
A primary dysfunction at the level of the
follicle may disrupt the hypothalamic-pituitary-ovarian axis and cause the formation
of COF (Fig. 1). First of all, alterations in
LH receptor expression and content may
cause anovulation of the follicle. The LH
surge initiates a complex multi-gene, multistep process in which timing is essential,
finally leading to ovulation of the pre-ovulatory follicle [77]. According to Kawate
et al. [78], FSH and LH receptor numbers
in granulosa cells of cysts are decreased
when compared to normal follicles, but this
is contradicted by data from Odore et al.
[79] and Calder et al. [80]. Discrepancies
between studies may be explained by differences in methodology such as demonstration of the receptor itself or its mRNA,
and the division of cysts into oestrogenactive and oestrogen-inactive. In the same
study, Calder et al. [80] also studied developing young cysts but no differences in
FSH/LH receptor mRNA were observed
when compared to dominant follicles.
Young cysts were, however, studied in the
presence of existing cysts, i.e. when the
endocrine environment was already altered,
and therefore the pathogenesis may differ
from primary developing cysts.
Another receptor of interest is the oestradiol receptor (ER-). In rodents, the importance of this receptor in follicular growth and
development has clearly been demonstrated

110

T. Vanholder et al.

[81, 82] and its localisation in follicle cells

throughout follicular development has been
described in many mammals including cattle [83, 84]. More specifically, in rat ovarian
follicles ER- mRNA expression precedes
increased expression of mRNA for the LH
receptor and specific steroidogenic enzymes
[85]. Therefore, alterations in ER- expression may be involved in the development of
COF. However, this hypothesis is not supported by data from Calder et al. [80] showing that ER- mRNA expression was not
altered in growing young cysts. Odore et al.
[79] did, however, find decreased oestrogen
receptor concentrations in follicular cysts,
but the oestrogen receptor type was not
defined.
Besides changes in receptor expression
and content, alterations in steroidogenesis by
the dominant follicle may also be involved
in cystic degeneration. After all, the dominant follicle has to elicit an LH surge at the
right time in its development by producing
sufficient oestradiol. Oestrogen-active cysts
show a higher expression of 3-hydroxysteroid dehydrogenase mRNA, a steroidogenic enzyme [80], and cows developing a
cyst have increased oestradiol concentrations
during the early stages of follicular dominance [86]. However, Calder et al. [80]
were unable to observe changes in mRNA
expression of steroidogenic enzymes in the
follicle wall of young growing cysts. They
concluded that alterations of the endocrine
system precede, and perhaps cause, the
observed follicular alterations in cysts. In
the study of Calder et al. [80], young cysts
did, however, develop in the presence of
existing cysts, i.e. when the endocrine environment was already altered. As a consequence, the mechanism causing these young
cysts to actually become cysts may differ
from the mechanism(s) involved in primary
cyst formation.
Apart from changes in mRNA expression for certain receptors and steroidogenic
enzymes, cell proliferation and apoptosis in
the granulosa and theca interna cell layers
also seem to be altered in cystic follicles.

Early cystic follicles show an increase

in apoptosis while cell proliferation is
decreased [87, 88]. Although it is hard to
establish a cause-effect relationship, alterations like these may disrupt normal follicle
growth and steroidogenesis leading to
cystic degeneration.
Recently, Imai et al. [89] suggested that
matrix metalloproteinases (MMP) could be
involved in the formation of cysts: higher
proMMP-2 and -9 levels were present in the
follicular fluid of cysts than in the follicular
fluid of normal dominant follicles. MMP
play a role in follicle wall remodelling and
rupture at the time of ovulation [77, 90], but
hereto the inactive proMMP form needs to
be transformed to the active MMP form.
This activation is triggered by the LH-surge
[77]. Since an aberrant LH-surge causes
COF formation, the higher proMMP-2 and
-9 levels in the follicular fluid of COF are
most likely an indication of the lack of an
LH-surge rather than a cause of COF formation.
4.3. Predisposing factors for COF
As mentioned before, COF are mainly
observed in high yielding dairy cows during
the first months post partum and milk yield
is generally considered a risk factor [40, 51,
88, 86, 9193], although not all authors
agree [37, 94]. Moreover, besides the fact
that a genetic predisposition for COF exists
(see above), a genetic correlation between
cysts and milk production traits has been
established, indicating that an ongoing
selection for production parameters will
increase the incidence of COF [51]. What
the genetic factor(s) are and how they promote the formation of cysts is not known.
However, the fact that cows do not develop
a cyst during every lactation and during
every ovarian cycle indicates that gene
expression may be promoted by, or gains
functional importance under, certain stressors, for example high milk yield and the
associated negative energy balance (NEB)
during the early postpartum period. At this

Cystic ovarian follicles in dairy cattle

time, energy requirements to sustain milk

yield are higher than energy intake thus
causing a NEB. This NEB is accompanied
by several hormonal and metabolic adaptations, affecting ovarian function [95]. Energy
balance may be a more accurate parameter
than milk yield to further elucidate the association between COF and production traits.
Some animals can compensate for higher
milk production through greater dry matter
intake reducing the effect of milk yield on
energy balance [92]. This could explain
why not all authors [37, 94] observed a correlation between ovarian cysts and milk
yield. However, when focussing on energy
balance and the occurrence of COF, the
results still remain inconclusive. While Zulu
et al. [24], Refsdal [43] and Sovani et al.
[96] observed a deeper NEB and increased
mobilization of body reserves in cows developing cysts, Beam [86] noticed that the
nadir of the NEB occurred later post partum
in cystic cows than in ovulatory cows.
Moreover, cystic cows even mobilized less
body reserves and derived a smaller percentage of their milk yield from body
weight loss [86]. Hooijer et al. [97] were
unable to find a more severe NEB, evaluated by the fat/protein ratio in milk, in cows
with COF compared to ovulatory cows.
However in an earlier study, Heuer et al.
[91] observed that a high fat/protein ratio,
and, therefore, a more severe NEB, increased
the risk of cyst occurrence. Data in sheep
also suggest that an increased mobilisation
of body reserves, indicative for a deeper
NEB, is linked with the occurrence of cystic
follicles [76]. Although a concensus is lacking, we conclude from the literature that a
link seems to exist between COF and the
magnitude and/or duration of the NEB.
The possible underlying mechanism(s)
is(are) also still unclear, but NEB may
affect COF formation at both the level of the
hypthalamus/pituitary and the ovary/follicle through associated hormonal and metabolic changes [98, 99] (Fig. 1). During NEB,
peripheral plasma concentrations of IGF-1,
insulin, glucose [95] and leptin [100, 101]
are reduced, while concentrations of metab-

111

olites such as non-esterified fatty acids

(NEFA) [102] and -hydroxybutyrate (BHB)
are increased [103]. The IGF-system plays
an important role in follicle growth and
development [104]. Besides a direct effect,
IGF-1 together with insulin indirectly stimulates follicular development through upregulation of the LH-receptor on granulosa
cells [105]. Therefore, low systemic IGF-1
concentrations early post partum could
contribute to anovulation and subsequent
development of cystic follicles as shown by
Zulu et al. [24]. However, data from Beam
[86] do not confirm this hypothesis. Also
insulin itself is known to be a potent stimulator of follicle cell steroidogenesis and
proliferation in vitro [106, 107] and in vivo
[108110]. Consequently, reduced circulating insulin concentrations early post partum may play a role in ovarian dysfunction
i.e. cyst formation, as we have recently
demonstrated [69]. Besides low insulin concentrations, a general state of peripheral
insulin resistance is present as well in high
yielding dairy cows early post partum [111,
112]. Insulin resistance is regarded as an
important factor in the pathogenesis of the
Polycystic Ovary Syndrome (PCOS) in
women [113115] and COF have often
been compared to this syndrome, justified
or not. However, insulin insufficiency rather
than insulin resistance has been observed in
COF cows [116], indicating an altered
interaction between glucose and insulin at
the pancreatic level. In addition, in ewes it
was not possible to induce cyst formation
through the establishment of a state of insulin resistance [76]. Conclusively, IGF-1
and insulin are important stimulators of follicle growth and based on the limited
number of publications on the subject, low
concentrations of one or both hormones
may contribute to the formation of COF
(Fig. 2). Further research should confirm
whether or not this hypothesis is valid.
Leptin is a recently new hormone, produced by adipocytes, and is regarded as the
ultimate factor linking metabolic status to
reproduction [117]. Depending on the metabolic state of the animal it either has a

112

T. Vanholder et al.

Figure 2. Schematic model of how low insulin and/or IGF-1 concentrations may cause cyst formation. Low insulin/IGF-1 concentrations insufficiently (+) stimulate follicle cell proliferation and oestradiol-17 production. The reduced oestradiol-17 feedback, together with the low insulin/IGF-1
concentrations result in a reduced gonadotropin release. Dominant follicle growth is retarded and
the altered follicular growth pattern and oestradiol-17 production disrupt the hypothalamo-pituitary-gonadal axis. This finally results in an aberrant LH-surge and the subsequent development of
a cystic follicle.

stimulatory effect or none at all on hypothalamic-pituitary function in cattle [118

120]. In the postpartum dairy cow, a clear
relationship between leptin profiles and
first postpartum ovulation is lacking [101],
although a minimum permissive level of
leptin seems required to induce the first
postpartum LH surge [101, 121]. Therefore, leptin may play a role in early post partum cyst development.
According to Zulu et al. [24] and
Huszenicza et al. [122] cows developing
cysts have higher serum NEFA concentrations during the first week(s) post partum
than ovulatory cows, although Beam [86]
was unable to observe this. Interestingly, in
rats, elevated NEFA concentrations for

48 h can decrease insulin secretion by the

-cells of the pancreatic islets in response
to a glucose challenge [123]. Moreover,
NEFA are cytotoxic for several cell types
[124127], including bovine granulosa and
theca cells [128, 129]. So (prolonged) exposure to high NEFA concentrations during
periods of NEB may hamper follicle growth
and development, disrupting the complex
endocrine system and promoting the formation of ovarian cysts.
Although elevated serum ketone concentrations increase the risk of delayed cyclicity [122, 130, 131] and cyst occurrence [132,
133] post partum, they do not exert any negative effects on bovine follicle cells in vitro
[134]. Consequently, ketone concentrations

Cystic ovarian follicles in dairy cattle

in the postpartum dairy cow seem to be an

indicator of the severity of the NEB, but not
a mediator of the negative effects of the
NEB on reproduction at the ovarian level.

5. CONCLUSION
Cystic ovarian follicles are one of the
most frequent and important ovarian disorders in modern high yielding dairy cows
that have been the subject of much research
in recent decades. However, many aspects
of the disease, and especially pathogenesis,
remain unclear and inconclusive, as for
example, illustrated by the lack of a clear
definition. In particular, the endocrine and
follicular changes that precede spontaneous
cyst formation are still unknown, mainly
due to the heterogeneity and unpredictability of the disease. Studies aimed at elucidating the pathogenesis, have tried to do so by
induction of cysts. This, however, may not
mimic naturally-occurring cysts. Nevertheless, such experiments have enhanced our
knowledge about the endocrine and follicular changes that occur after cyst formation.
Development of an accurate model mimicking the in vivo situation or identification
of criteria to allow classification of a follicle
as a future cyst before it actually becomes
cystic, would be very valuable in studying
the cellular and molecular changes that precede ovarian cyst formation.
Due to the genetic correlation with production traits and the high incidence of
ovarian cysts during the period of NEB
early post partum, future research should
also focus on the effect of NEB-associated
metabolic/hormonal changes and energy
utilisation on follicular development and
steroidogenesis. Understanding how NEB
affects cyst formation will help to optimise
management and feeding practices in preventing the occurrence of ovarian cysts/
COF.
Further research on cellular changes in
follicular cysts may elucidate which genes
show an altered expression pattern com-

113

pared to normal dominant follicles and

could therefore be involved in the primary
development. Genetic knock-out models as
well may help to determine which genes
play a role in cyst formation. The identification of these genes would be an initial
step in the process of identifying the hereditary factor(s), making it possible to genetically screen bulls and cows for COF prior
to their use in artificial insemination programmes.

ACKNOWLEDGEMENTS
T. Vanholder is supported by a fellowship
from the Special Research Fund, Ghent University, grant No. 011D8501.

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